Sequential rhodium-, silver-, and gold-catalyzed synthesis of fused dihydrofurans

Article abstract of DOI:10.1021/ol2016548

A triple cascade process was developed for the rapid synthesis of polycyclic benzo-fused dihydrofurans. The first step is a rhodium-catalyzed cyclopropanation of α-aryldiazoketones with alkenes. This is followed by a silver-catalyzed ring expansion to dih

Full text of DOI:10.1021/ol2016548

ORGANIC
LETTERS
2011
Vol. 13, No. 16
4316–4319
Sequential Rhodium-, Silver-, and
Gold-Catalyzed Synthesis of Fused
Dihydrofurans
Hengbin Wang,† Justin R. Denton,‡ and Huw M. L. Davies*,†
Department of Chemistry, Emory University, 1515 Dickey Drive, Atlanta, Georgia
30322, United States, and Department of Chemistry, University at Buffalo, The State
University of New York, Buffalo, New York 14260-3000, United States
hmdavie@emory.edu
Received June 20, 2011
ABSTRACT
A triple cascade process was developed for the rapid synthesis of polycyclic benzo-fused dihydrofurans. The first step is a rhodium-catalyzed
cyclopropanation of R-aryldiazoketones with alkenes. This is followed by a silver-catalyzed ring expansion to dihydrofurans, which then undergo
a gold-catalyzed cyclization to form benzo-fused dihydrofurans.
A feature of the metal-catalyzed reactions of diazo
compounds is the formation of highly energetic metal-
carbenoid intermediates under very mild reaction condi-
tions. The resulting carbenoid reactions often generate
strained or reactive products, capable of undergoing
further transformations.1,2 Our group has developed a
variety of cascade reactions using carbenoid intermediates,
such as ylide formation/[3 þ 2] cycloaddition,3 ylide
formation/[2,3] sigmatropic rearrangement,4 and cyclo-
propanation/Cope rearrangement.5 An alternative way
of achieving a cascade sequence is to conduct a further
metal-catalyzed transformation through multicatalytic
processes.6 We have been interested in developing syn-
thetic sequences that combine the rhodium-catalyzed reac-
tions with other complementary metal-catalyzed reactions
with orthogonal reactivity.7 In this paper we describe a
triple cascade sequence that involves sequential rhodium-,
silver-, and gold-catalyzed reactions.
† Emory University.
‡ University at Buffalo, The State University of New York.
(1) For reviews: (a) Doyle, M. P.; Duffy, R.; Ratnikov, M.; Zhou, L.
Chem. Rev. 2010, 110, 704. (b) Padwa, A. Chem. Soc. Rev. 2009, 38, 3072.
(c) Padwa, A. J. Org. Chem. 2009, 74, 6421. (d) Davies, H. M. L.;
Beckwith, R. E. Chem. Rev. 2003, 103, 2861. (e) Padwa, A.; Weingarten,
M. D. Chem. Rev. 1996, 96, 223.
(5) For examples: (a) Schwartz, B. D.; Denton, J. R.; Lian, Y.;
Davies, H. M. L.; Williams, C. M. J. Am. Chem. Soc. 2009, 131, 8329.
(b) Olson, J. P.; Davies, H. M. L. Org. Lett. 2008, 10, 573. (c) Reddy,
R. P.; Davies, H. M. L. J. Am. Chem. Soc. 2007, 129, 10312. (d) Davies,
H. M. L.; Loe, Ø.; Stafford, D. G. Org. Lett. 2005, 7, 5561.
(2) For recent examples: (a) Jiang, J.; Xu, H.; Xi, J.; Ren, B.; Lv, F.;
Guo, X.; Jiang, L.; Zhang, Z.; Hu, W. J. Am. Chem. Soc. 2011, 133, 8428.
(b) Zhu, Y.; Zhai, C.; Yang, L.; Hu, W. Eur. J. Org. Chem. 2011, 1113. (c)
Hu, W.; Xu, X.; Zhou, J.; Liu, W.; Huang, H.; Hu, J.; Yang, L.; Gong, L.
J. Am. Chem. Soc. 2008, 130, 7782. (d) Liu, Y.; Bakshi, K.; Zavalij, P.;
Doyle, M. P. Org. Lett. 2010, 12, 4304. (e) England, D. B.; Padwa, A. J.
Org. Chem. 2008, 73, 2792.
(6) For examples: (a) Guan, X.; Yang, L.; Hu, W. Angew. Chem., Int.
Ed. 2010, 49, 2190. (b) Guo, Z.; Cai, M.; Jiang, J.; Yang, L.; Hu, W. Org.
Lett. 2010, 12, 652. (c) Davi, M.; Lebel, H. Chem. Commun. 2008, 4974.
ꢀ
(d) Lebel, H.; Ladjel, C.; Brethous, L. J. Am. Chem. Soc. 2007, 129,
13321.
(7) (a) Deng, L.; Giessert, A. J.; Gerlitz, O. O.; Dai, X.; Diver, S. T.;
Davies, H. M. L. J. Am. Chem. Soc. 2005, 127, 1342. (b) Ni, A.; France,
J. E.; Davies, H. M. L. J. Org. Chem. 2006, 71, 5594.
(3) Lian, Y.; Davies, H. M. L. J. Am. Chem. Soc. 2010, 132, 440.
(4) Li, Z.; Davies, H. M. L. J. Am. Chem. Soc. 2010, 132, 396.
r
10.1021/ol2016548
Published on Web 07/19/2011
2011 American Chemical Society

In recent years, homogeneous gold-catalyzed reactions
have developed rapidly.8 One class of gold-catalyzed reac-
tions is the cycloisomerization of alkynyl cyclopropane
derivatives.9 Recently, we explored the rhodium-catalyzed
asymmetric cyclopropanation chemistry of R-aryldi-
azoketones.10 During the course of the optimization studies
of this chemistry, we discovered that alkynyl-substituted
diazo compounds were the optimum substrates for high
asymmetric induction. As the resulting products have multi-
ple reactive sites, such as the cyclopropyl ketone and the
alkyne functionality, we considered that they would be ideal
substrates for multiple metal-catalyzed cascade processes.
Table 1. Optimization of the Cycloaddition Reaction
solvent
(v/v)
temp time ratioa yieldb
Scheme 1. Initial Study of the Gold-Catalyzed Cycloaddition
Reaction
entry
L AuCl
(°C)
(h)
(7:8:9)
(%)
3
1
2
3
4
5
AuCl
DCM
reflux 24
reflux 0.5
reflux 0.5
2.4:1:1
2.8:1:0
2.0:1:0
2.5:1:0
1.6:1:0
59c
78
83
99
91
Ph3PAuCl DCM
Ph3PAuCl DCE
Ph3PAuCl PhMe
85
0.5
Ph3PAuCl DCM/PhMe reflux 0.5
(1/1)
6
Ph3PAuCl DCM/PhMe reflux 0.5
(1/2)
1.8:1:0
99
a Determinded by crude NMR. b Combined yield of compounds 7
and 8. c Combined yield of compounds 7, 8, and 9.
is electrophilic and would require an electron-rich aro-
matic ring for effective ring closure.11 Therefore the reac-
tion sequence was repeated with the m-methoxy derivative
5 (Table1). Under these conditionsthe dihydrobenzofuran
derivatives 7 and 8 were observed, together with an
uncyclized dihydrofuran compound 9 (entry 1). Complete
cyclization was achieved when chlorotriphenylphosphine
gold(I) (PPh3AuCl) was used as a catalyst (entry 2).
Further optimization studies showed that toluene was the
ideal solvent for this gold-catalyzed cycloaddition reaction
and the polycyclic products were isolated in nearly quanti-
tative yield (entry 4). A similar yield was also obtained after
switching to a cosolvent system consisting of a 1:2 volume
ratio of DCM and toluene (entry 6). As will be discussed
later, the mixed-solvent system became the foundation of a
one-pot cascade sequence for this transformation.
The study began with the reaction of the p-chlorophe-
nyldiazoketone 1 (Scheme 1). Rhodium-catalyzed cyclo-
propanation between 1 and styrene generated the cyclo-
propyl ketone 2 in 90% yield. Treatment of 2 with silver
triflate (AgOTf) and tetrabutylammonium fluoride resulted
in desilylation and ring expansion to form 3. The third
metal-catalyzed step was projected to be a gold-catalyzed
cyclization of the alkyne to generate the fused polycyclic
compound 4. However, under a variety of reaction condi-
tions, no more than trace amounts of the polycyclic product
were observed starting from either compound 2 or 3.
A possible explanation for the failure of the gold-cata-
lyzed cyclization could be that the gold-activated complex
(8) For recent reviews: (a) Krause, N.; Winter, C. Chem. Rev. 2011,
ꢀ
111, 1994. (b) Corma, A.; Leyva-Perez, A.; Sabater, M. J. Chem. Rev.
ꢀ
Scheme 2. Possible Mechanism of the Cycloaddition Reaction
ꢀ~
2011, 111, 1657. (c) Jimenez-Nunez, E.; Echavarren, A. M. Chem. Rev.
2008, 108, 3326. (d) Li, Z.; Brouwer, C.; He, C. Chem. Rev. 2008, 108,
3239. (e) Furstner, A.; Davies, P. W. Angew. Chem., Int. Ed. 2007, 46,
€
3410. (f) Marion, N.; Nolan, S. P. Angew. Chem., Int. Ed. 2007, 46, 2750.
ꢀ
(9) (a) Barluenga, J.; Tudela, E.; Vicente, R.; Ballesteros, A.; Tomas,
M. Angew. Chem., Int. Ed. 2011, 50, 2107. (b) Kleinbeck, F.; Toste, F. D.
J. Am. Chem. Soc. 2009, 131, 9178. (c) Gorin, D. J.; Watson, I. D. G.;
Toste, F. D. J. Am. Chem. Soc. 2008, 130, 3736. (d) Zhang, X.; Tu, Y.;
Jiang, Y.; Zhang, Y.; Fan, C.; Zhang, F. Chem. Commun. 2009, 4726.
(e) Zhang, G.; Huang, X.; Li, G.; Zhang, L. J. Am. Chem. Soc. 2008, 130,
1814. (f) Zhang, J.; Schmalz, H. G. Angew. Chem., Int. Ed. 2006, 45,
6704.
(10) Denton, J. R.; Davies, H. M. L. Org. Lett. 2009, 11, 787.
(11) (a) Watanabe, T.; Oishi, S.; Fujii, N.; Ohno, H. Org. Lett. 2007,
~
~
9, 4821. (b) Nieto-Oberhuber, C.; Munoz, M. P.; Bunuel, E.; Nevado,
ꢀ
C.; Cardenas, D. J.; Echavarren, A. M. Angew. Chem., Int. Ed. 2004, 43,
2402.
Org. Lett., Vol. 13, No. 16, 2011
4317

A reasonable mechanism for the sequential reactions is
shown in Scheme 2. AgOTf is expected to act as a Lewis
acid and induce rearrangement of the cyclopropyl ketone
10 to form the dihydrofuran 11. The following gold-
catalyzed benzannulation would be expected to form 12,
which upon deprotonation and proto-demetalation would
afford the tricyclic product 13.
cyclopropanation and the cycloaddition reactions pro-
ceeded in excellent yields. The cycloaddition reaction of
the 2-naphthyl derivative 15d generated the tetracyclic
product 16d as a single regioisomer in high yield. The
structure of 16d was confirmed by X-ray crystallographic
analysis.12 The same selectivity was also observed for the
other 2-naphthyl derivatives 16e and 16f.
Table 2. Sequential Reactions of Diazo Ketones with Styrene
Table 3. Sequential Reactions of 14a with Alkenes
a The reactions were monitored by TLC, and heating was stopped
when all the starting materials were consumed. b Isolated yields.
The reactions with the trimethoxy derivative 14a were
applied to a range of alkenes (Table 3). Different reactiv-
ities were observed for the gold-catalyzed reactions of
cyclopropane derivatives originating from electron-rich
styrenes compared to electron-poor styrenes. The reaction
with 4-methoxystyrene provided the polycyclic product
18c in low yield. In contrast, the reaction with 4-
(trifluoromethyl)styrene produced 18d in excellent yield.
The attempted annulation of 19, which was derived from
14a and indene, gave an unexpected result because it
produced not only the expected product 20 but also phenol
21 (Scheme 3). The structure of 21 was confirmed by X-ray
crystallography.12 All efforts of converting 20 to 21, with
silver or gold catalysts, or trifluoromethanesulfonic acid,
were unsuccessful. This suggested that 20 and 21 are
formed by different reaction pathways as indicated in
compound 22: the normal route (route a) constructed 20,
and the other one (route b) would lead to intermediate
23. This intermediate could then undergo aromatization,
protonation, and gold-catalyzed benzannulation to provide
24. Thefollowing proto-demetalation and tautomerization
would supply the pentacyclic product 21.
a The reactions were monitored by TLC, and heating was stopped
when all the starting materials were consumed. b Isolated yields.
To explore the scope of this method, several diazo
compounds were subjected to this sequence (Table 2).
Although compounds 15a and 15b are more sterically
hindered than compound 6, with a methoxy group on
each side of the phenyl ring, polycyclic products 16a
and 16b were obtained in high yields after a period of
2 h. With the 3,5-dimethylphenyl derivative 15c, both the
(12) The crystal structures of 16d and 21 have been deposited at the
Cambridge Crystallographic Data Centre under deposition numbers
CCDC 827585 and 827586 respectively.
4318
Org. Lett., Vol. 13, No. 16, 2011

Table 4. Examples of the One-Pot Procedure
Scheme 3. Conversion of 19 to 20 and 21
reaction time
isolated yield
entry
product
of step 2 (h)
16aꢀd (%)
1
2
3
4
16a
16b
16c
16d
2
2
3
2
74
74
82
72
In summary, a class of polycyclic dihydrofuran deri-
vatives was synthesized in high yields by means of three
sequential transition-metal-catalyzed reactions. A one-
pot procedure for this transformation was also estab-
lished. This sequence illustrates the potential of carbe-
noid chemistry to initiate a cascade sequence of
reactions. The application of this method to the syn-
thesis of natural products is currently ongoing in our
laboratory.
A one-pot procedure was also developed for this se-
quential reaction (Table 4). This was based on the success-
ful cycloaddition reaction employing the cosolvent system
of DCM/toluene. The first step is the rhodium-catalyzed
cyclopropanation reaction with DCM as solvent. After
finishing this step, the reaction was cooled down to room
temperature. To this solution at room temperature was
added the silver and gold catalysts and toluene. The
resulting mixture was heated to reflux again, and the
reaction was monitored by TLC. Heating was stopped
after all of the cyclopropane had been consumed. This
one-pot procedure resulted in the formation of 16aꢀd in
similar yields to the two-step sequence (Table 2).
Acknowledgment. Financial support of this work by
the National Science Foundation (CHE 0750273) is grate-
fully acknowledged. We thank Dr. Ken Hardcastle, Emory
University, for the X-ray crystallographic analysis.
Supporting Information Available. Experimental pro-
cedures and characterization and spectral data for new
compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 16, 2011
4319